Author
Trujillo, MarissaIssue Date
2024Advisor
Galligan, James J.
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The University of Arizona.Rights
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Release after 01/01/2027Abstract
Post-translational modifications (PTMs) can alter the structure and function of proteins, allowing them to play vital roles in cell signaling, regulation of enzymatic activity, or protein localization. The source for these PTMs is endogenous metabolites, and research has focused on understanding the regulation and generation of these PTMs, primarily those that are generated via enzymatic means. One of the best examples of an enzymatic PTM is the acetylation of Lys residues generated by the important signaling molecule, acetyl-CoA. The addition and removal of these different moieties is regulated by enzymatic “writers” and “erasers,” respectively. Although many PTMs do occur via enzymatic means, there has been rising interest in the generation of non-enzymatic PTMs. Similarly, these PTMs are generated via endogenous metabolites, however, their addition and removal occur with no enzyme. Arguably, this could lead to over-abundance, or non-specificity of these PTMs on proteins, leading to signaling dysfunction. However, we and others have demonstrated that these PTMs can play important regulatory roles for metabolic signaling and feedback. Our lab has previously identified a novel PTM, generated from the reactive metabolic intermediate, methylglyoxal (MGO). Due to the reactivity and supposed toxicity of MGO, all cells are equipped with the glyoxalase cycle, which contains the two enzymes, glyoxalase 1 (GLO1) and GLO2. First, MGO is conjugated to glutathione (GSH) to form a hemithioacetal (HTA). GLO1 then isomerizes this HTA to form the intermediate, lactoylglutathione (LGSH). GLO2 then hydrolyzes LGSH to form D-lactate and reintroduce GSH back into the glyoxalase cycle. Our previous data has demonstrated the generation of lactoylLys, via the non-enzymatic S-to-N acyl transfer from LGSH onto free Lys residues. We and others have since demonstrated a regulatory role for lactoylLys on histones in inflammation. Additionally, MGO itself is the source for the non-enzymatic PTMs: carboxyethylArg (CEA), carboxyethylLys (CEL), and methylglyoxal-hydroimidazolone 1 (MG-H1). These PTMs, as well as MGO itself have historically been linked to many different metabolic diseases including aging, cancer, anddiabetes. The following studies demonstrate the regulatory role of both GLO1 and GLO2 in different metabolic diseases. We demonstrate the role of GLO1 in regulating adipogenesis. In contrast, we demonstrate a regulatory role of GLO2 in Ser biosynthesis, by regulating the enzymatic activity of the first enzyme in the Ser biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH). Collectively, we demonstrate an important role for non-enzymatic PTMs and how they regulate important cell signaling pathwaysType
textElectronic Dissertation
Degree Name
Ph.D.Degree Level
doctoralDegree Program
Graduate CollegePharmacology & Toxicology